Skeletal muscle contraction is ultimately initiated by activity in the nervous system. Muscle receives both sensory and motor nerve fibres. The sensory nerves convey information about the state of the muscle to the nervous system. This includes information about muscle length detected by the muscle spindles and tension detected by the Golgi tendon organs. There are also a variety of free nerve endings in the muscle tissue, some of which convey sensations of pain. Of the motor fibres in mammals, the γ-motoneurons provide a separate motor nerve supply for the muscle fibres of the muscle spindles. However, the bulk of the muscle fibres are supplied by the α-motoneurons. Each α-motoneuron innervates a number of muscle fibres, from less than ten in the extraocular muscles, which move the eyeball in its socket, to over a thousand in a large limb muscle. The complex of one motoneuron plus the muscle fibres which it innervates is called a motor unit. Since they are all activated by the same nerve cell, all the muscle fibres in a single motor unit contract at the same time. However, muscle fibres belonging to different motor units may well contract at different times. Thus, most mammalian muscle fibres are contacted by a single nerve terminal, although sometimes there may be two terminals originating from the same nerve axon. Muscle fibres of this type are known as twitch fibres, since they respond to nervous stimulation with a rapid twitch.

Epilepsy, autism and cognitive impairment are over-represented in all studies that take one of these major categories as the starting point. The rates of epilepsy and autism are related to the severity of cognitive impairment. Those with primary or early regressive autism show a steadily rising rate of epilepsy with age reaching 30–50% in some adult studies but without evidence of causative relationship. Seizures of all types occur with complex partial attacks being prominent but we have no convincing explanation for this relationship. However, in several particularly early onset epilepsies, autism and cognitive impairment develop with the epilepsy suggesting causation (i.e. an epileptic encephalopathy). This process seems to preferentially involve the temporal neocortex and medical or surgical treatment of the epilepsy may cause remission of autistic symptoms in these cases.

Introduction

In 1943, Kanner described 11 children with his then new ‘autistic disturbances of affective contact’ (Kanner, 1943). One of these 11 suffered from epilepsy. In 1971, Kanner reported on a follow-up of the 11 patients; by now, two patients – 18% of his original series – were suffering from epilepsy (Kanner, 1971). Thus, in this seminal report, which defined autism, the patients already formed a clinically heterogeneous group – those with and those without seizures.

What has become clear over the years since Kanner's writings is that patients with autism are, in fact, at greater risk of seizures than are children with other types of developmental problems, such as developmental dysphasia or Down syndrome (Wong, 1993).

There are important social-developmental contributions to the acquisition of flexible, generative, context-sensitive thinking and engagement with the world. We highlight how among individuals with autism, limitations in the propensity to identify with the attitudes of other people might lead to a paucity of movement across alternative ‘takes’ on the world, and with this, specific forms of cognitive restriction and rigidity.

Introduction

Consider this condensed version of a classic description of a person with autism called L (Scheerer et al. 1945). L was first seen at the age of 11 with a history of severe learning difficulties. He was said never to have shown interest in his social surroundings. Although he had an IQ of only 50 on a standardised test of intelligence, L could recount the day and date of his first visit to a place, and could usually give the names and birthdays of all the people he met there. He could spell forwards and backwards.

L's background history included the fact that in his fourth and fifth years he rarely offered spontaneous observations or reasons for any actions or perceived event. Nor would he imitate an action of others spontaneously. He was unable to understand or create an imaginary situation. He did not play with toys, nor did he show any conception of make-believe games. He was unable to converse in give-and-take language. He barely noticed the presence of other children, and was said to have ‘little emotionality of normal depth and coherence’.

Since autism was first described in 1943, it has become evident that the condition is one of the most heritable of all the childhood onset neurodevelopmental disorders. In this chapter we chart the progress of researchers' attempts to understand the genetic components of autism spectrum disorders and how these studies have tracked the advances in technology and knowledge in the field of genetics in general. We start by describing the evidence that autism spectrum disorders have such a strong genetic component. We then consider approaches to identify susceptibility genes such as linkage, candidate gene studies and association analysis. Various epigenetic mechanisms of potential relevance to autism as well as the expanding area of copy number variations are also highlighted. Some of the theoretical background to each of these approaches is given and findings from each approach are summarized and discussed. In addition, several specific examples are given for each method to demonstrate in detail the way in which they have been employed to yield key successes within the field of autism genetics. Finally, we look towards the future and suggest possible further avenues of investigation, as well as newly arising challenges, in this difficult, yet exciting field of study.

Evidence for genetic liability and the multifactorial model for autism

In 1943, Leo Kanner, an Austrian psychiatrist, was the first to describe a condition observed in a group of eleven children with developmental abnormalities, a disorder that today is known as autism (Kanner, 1943).

The processes described in the preceding chapters culminate in the generation of mechanical activity by skeletal muscle. These mechanical properties of muscles are readily investigated using isolated muscle or nerve–muscle preparations such as the gastrocnemius or sartorius nerve–muscle preparations in the frog. Experiments on large mammalian muscles require an intact blood supply, in which case the experiments must be performed on an anaesthetized animal, with the nerve supply to the muscle cut and its tendon dissected free and attached to some recording device. The muscle is excited by applying a brief pulse of stimulating current to its nerve or directly to the muscle itself.

Isometric and isotonic contractions

When muscles contract they exert a force on their attachments (this force is equal to the tension in the muscle) and they shorten if they are permitted to do so. Hence we can measure two different variables during the contraction of a muscle: its length and its tension. Most often one of these two is maintained constant during the contraction. In isometric contractions the muscle is not allowed to shorten (its length is held constant) and the tension it produces is measured. In an isotonic contraction the load on the muscle (which is equal to the tension in the muscle) is maintained constant and its shortening is measured.

An isometric recording device has to be stiff, so that it does not in fact allow the muscle to shorten appreciably while the force is being measured.

Clinical experience and anecdotal written accounts suggest that school-age children with high-functioning autism spectrum disorders (ASD) have difficulties which can be described as ‘executive dysfunction’. Problems with organisation, planning and task completion impede academic achievement and cause disruption in daily routine. The authors review research of executive function in this population and conclude that clinicians will find little in the scientific literature to guide them in neuropsychological assessment and remediation. They describe their study of 23 clinic-referred children (18 boys, 5 girls; mean age of 9) illustrating the challenges facing clinicians who would measure executive function. Tests of executive function (including the NEPSY and the BADS-C) were administered. Parent and Teacher questionnaires (DEX-C, BRIEF and VABS) were completed. Scores on tests of executive function and other areas of cognition were found to be in the average or above average range. In contrast, responses on both teacher and parent questionnaires indicated significant executive dysfunction. Parents' responses on the BRIEF and on the DEX-C were not correlated with teacher responses on the BRIEF. The authors consider the importance of a “halo effect” on questionnaire responses and challenge the notion that questionnaire measures have more ecological validity than laboratory measures. Suggestions for future research include observation, interviews and graded modification of the testing environment.

Introduction

Not enough attention is given to identifying individual neuropsychological deficits of children with ASD in the clinical setting with the aim of remediation despite being recommended by the National Autism Plan for Children (2003).

Electrophysiological recording methods

Although the nervous impulse is accompanied by effects that can under especially favourable conditions be detected with radioactive tracers, or by optical and thermal techniques, electrical recording methods normally provide much the most sensitive and convenient approach. A brief account is therefore necessary of some of the technical problems that arise in making good measurements both of steady electrical potentials and rapidly changing ones.

In order to record the potential difference between two points, electrodes connected to a suitable amplifier and recording system must be placed at each of them. If the investigation is only concerned with action potentials, fine platinum or tungsten wires can serve as electrodes, but any bare metal surface has the disadvantage of becoming polarized by the passage of electric current into or out of the solution with which it is in contact. When, therefore, the magnitude of the steady potential at the electrode tip is to be measured, non-polarizable or reversible electrodes must be used, for which the unavoidable contact potential between the metal and the solution is both small and constant. The simplest type of reversible electrode is provided by coating a silver wire electrolytically with AgCl, but for the most accurate measurements calomel (Hg/HgCl2) half-cells are best employed.

When the potential inside a cell is to be recorded, the electrode has to be very well insulated except at its tip, and so fine that it can penetrate the cell membrane with a minimum of damage and without giving rise to electrical leaks.

Both voltage-gated and ligand-gated ion channels are large protein molecules, as is the sodium pump Na,K-ATPase. In recent years the primary structure of a number of them has been determined, and by combining this information with the biophysical evidence, major advances have been made in our understanding of how they work at the molecular and submolecular levels.

cDNA sequencing studies

A protein consists of a long chain built up of 20 different amino acids (Table 5.1), folded on itself in a rather complicated way. Its properties depend critically on the arrangement of the folds, which is determined by the exact order in which its constituent amino acids are strung together. This in turn is specified by the sequence of the nucleotide bases that make up the DNA molecules which constitute the genetic material of the cell. There are only four different bases, and each of the 20 amino acids corresponds according to a universally obeyed triplet code to a specific group of three of them. The information embodied in the base sequence of a DNA molecule is transcribed on to an intermediary messenger RNA, and is then translated during the synthesis of the protein to yield the correct sequence of amino acids. Rapid sequencing methods for nucleotides were perfected by Sanger and his colleagues, and modern recombinant DNA technology makes possible the cloning of DNA so that the quantity required for the determination can be prepared from a single gene.

Structure of the cell membrane

All living cells are surrounded by a plasma membrane composed of lipids and proteins, whose main function is to control the passage of substances into and out of the cell. In general, the role of the lipids is to furnish a continuous matrix that is impermeable even to the smallest ions, in which proteins are embedded to provide selective pathways for the transport of ions and organic molecules both down and against the prevailing gradients of chemical activity. The ease with which a molecule can cross a cell membrane depends to some extent on its size, but more importantly on its charge and lipid solubility. Hence the lipid matrix can exclude completely all large water-soluble molecules and also small charged molecules and ions, but is permeable to water and small uncharged molecules like urea. The nature of the transport pathways is dependent on the specific function of the cell under consideration. In the case of nerve and muscle, the pathways that are functionally important in connection with the conduction mechanism are: (1) the voltage-sensitive sodium and potassium channels peculiar to electrically excitable membranes, (2) the ligand-gated channels at synapses that transfer excitation onwards from the nerve terminal, and (3) the ubiquitous sodium pump, which is responsible in all types of cell for the extrusion of sodium ions from the interior.

The essential feature of membrane lipids that enables them to provide a structure with electrically insulating properties, i.e. to act as a barrier to the free passage of ions, is their possession of hydrophilic (polar) head groups and hydrophobic (non-polar) tails.

Autism is currently defined in terms of a core set of behaviours, including difficulties in social reciprocity and communication, and limitations in behavioural flexibility. In the past three decades, considerable efforts have been directed towards understanding the neurocognitive atypicalities that underlie these core behaviours. This chapter provides an overview of the major theoretical accounts of autism, especially the theory of mind hypothesis, the executive dysfunction hypothesis, and weak central coherence theory, each of which has aimed to explain autism in terms of a single underlying cognitive atypicality. Some of the reasons why researchers have become dissatisfied with these so-called ‘single-deficit’ accounts as explanatory models of autism will be analysed, before turning to more recent ‘multiple-deficits’ models to begin the task of outlining the additional challenges faced by such models. The chapter concludes by stressing the need to situate explanatory accounts of autism – single or multiple-deficit models – within a developmental context.

Introduction

Since the seminal experimental work of psychologists such as Hermelin and O'Connor (1970) and Frith (1970, 1972), considerable research efforts have been directed towards elucidating the psychological mechanisms underpinning the behavioural manifestations of autism spectrum disorder (hereafter ‘autism’), including the often profound difficulties in social reciprocity and communication, and stereotyped, repetitive interests and activities. Historically, in the interests of parsimony, researchers focused their efforts on isolating a single primary cognitive deficit that could provide a unifying explanation for the constellation of symptoms that are unlikely to co-occur by chance (Morton and Frith, 1995) (see also Rutter, 1968; 1983).